title: Novel highly potent serotonin 5-HT7 receptor ligands: structural modifications to improve pharmacokinetic properties.
abstract: Here we report the synthesis, pharmacological and pharmacokinetic evaluation of a pilot set of compounds structurally related to the potent and selective 5-HT7 ligand LP-211. Among the studied compounds, N-pyridin-3-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (4b) showed high affinity for 5-HT7 receptors (K(i)=23.8 nM), selectivity over 5-HT1A receptors (>50-fold), in vitro metabolic stability (82%) and weak interaction with P-glycoprotein (BA/AB=3.3). Compound 4b was injected ip in mice to preliminarily evaluate its distribution between blood and brain.
authors.affiliation: Università degli Studi di Bari 'Aldo Moro', Dipartimento di Farmacia-Scienze del Farmaco, via Orabona, 4, 70125 Bari, Italy. Electronic address: enza.lacivita@uniba.it.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Di Pilato
authors.forename: Madia Letizia
authors.initials: ML
authors.lastname: Stama
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Bianca
authors.initials: B
authors.lastname: De Filippis
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
authors.forename: Walter
authors.initials: W
authors.lastname: Adriani
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000577:Amides / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D010879:Piperazines / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000577:Amides; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor
keywords: 5-HT(7) receptors; Arylpiperazines; Microsomial S9 fraction; Serotonin